Inhibition of cell growth in CaCO2 cells by the polyamine analogue N1,N12-bis(ethyl)spermine is preceded by a reduction in MYC oncoprotein levels.
The polyamine analogue N1,N12bis(ethyl)spermine (BESpm) is a potent inhibitor of cell proliferation and is representative of a class of agents currently in clinical trials. Previous studies have demonstrated that BESpm treatment can produce a decrease in the mRNA levels of the protooncogene c-myc resulting from decreased transcription. Investigation into the mechanism of the antiproliferative effect of BESpm in the colon cancer cell line CaCO2 indicated that significant reduction in MYC protein, but not c-myc mRNA levels, preceded cytostasis. Specificity of the downregulation of MYC expression by BESpm treatment was demonstrated by comparison to effects on the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SSAT) and the polyamine biosynthetic enzyme ornithine decarboxylase (ODC). SSAT activity rapidly increased while levels of ODC activity decreased after BESpm treatment. Measurement of intracellular polyamines demonstrated significant uptake of the analogue after 24 hours, which was concurrent with a reduction of spermine and spermidine levels. Thus, cellular uptake of BESpm mediated a reduction of polyamine levels that was associated with a decrease of MYC protein at the post-transcriptional level.
Berchtold
C M
CM
Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
Tamez
P
P
Kensler
T W
TW
Casero
R A
RA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis; D004789:Enzyme Activation / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D009955:Ornithine Decarboxylase / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D013096:Spermine / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D011073:Polyamines; D016271:Proto-Oncogene Proteins c-myc; D013096:Spermine; C052614:N(1), N(12)-diethylspermine; D009955:Ornithine Decarboxylase; D004264:DNA Topoisomerases, Type I